The present invention provides novel halohydrin compounds, sulfone compounds and triene compounds which are useful intermediates for producing Vitamin A and processes for producing the intermediate compounds and Vitamin A.
The present invention provides:
1. A compound of the formula[I]: 
wherein R represents a hydrogen atom or a protective group for a hydroxyl group; and
A represents a hydrogen atom, a halogen atom or a group of the formula A1: 
xe2x80x83wherein Ar represents an aryl group which may be substituted; and
when A represents A1, Q represents Q3: 
xe2x80x83wherein R1 represents a hydrogen atom or a protective group for a hydroxyl group;
when A represents a halogen atom, Q represents Q3 as defined above or Q4: 
xe2x80x83wherein R2 represents a hydrogen atom or a protective group for a hydroxyl group;
when A represents a hydrogen atom, Q is Q2: 
2. A process for producing retinol of the formula [X] 
which comprises the steps of:
(a) subjecting a compound of the formula [III]: 
xe2x80x83wherein Rxe2x80x2 represents a protective group for a hydroxyl group, to a reaction in the presence of a titanium tetrachloride, and
(b) reacting the resulting compound in step (a) with a base(hereinafter referred to as xe2x80x9cProcess Axe2x80x9d);
3. A process for producing a compound of the formula [III]: 
wherein Ar is an aryl group which may be substituted and Rxe2x80x2 is a protective group for a hydroxyl group, which comprises reacting a compound of the formula [IV]: 
wherein Ar is the same as defined above, with a protective agent in the presence of a base and a phase transfer catalyst(hereinafter referred to as xe2x80x9cProcess Bxe2x80x9d);
4. A process for producing a compound of the formula [V]: 
wherein Ar represents an aryl group which may be substituted, R10 and Rxe2x80x2 are the same or different and represent a protective group for a hydroxyl group, which comprises reacting a sulfone compound of the formula[VI]: 
wherein Ar is the same as defined above, with a halohydrin compound of the formula [VII]: 
wherein R10 and Rxe2x80x2 are as defined above, and X represents a halogen atom, in the presence of a base (hereinafter referred to as xe2x80x9cProcess Cxe2x80x9d);
5. A process for producing a halohydrin compound of the formula [VIIxe2x80x2]: 
wherein R12 represents an acyl group and Rxe2x80x2 represent a protective group for a hydroxyl group, and X represents a halogen atom, which comprises reacting at least one halohydrin compound selected from the group consisting of a compound of the formula [VIIxe2x80x2a]: 
and a compound of the formula [VIIxe2x80x2b]: 
wherein R11 represents an acyl group or a hydrogen atom and Rxe2x80x2 represents a protective group for a hydroxyl group, with a carboxylic acid of the formula:
R12OH
wherein R12 is the same as defined above, in the presence of a strong acidic catalyst(hereinafter referred to as xe2x80x9cProcess Dxe2x80x9d);
6. A process for producing at least one halohydrin compound selected from the group consisting of the formula [VIIxe2x80x2a]: 
a compound of the formula [VIIxe2x80x2b]: 
wherein R11 represents an acyl group or a hydrogen atom and Rxe2x80x2 represents a protective group for a hydroxyl group, which comprises reacting a triene compound of the formula [VIII]: 
wherein Rxe2x80x2 is the same as defined above, with a halogenating agent and a compound of the formula:
R11OH
wherein R11 is is the same as defined above (hereinafter referred to as xe2x80x9cProcess Exe2x80x9d); and
7. A process for producing the triene compound of the formula [VIII] as defined above, which comprises reacting a compound of the formula [IX]: 
wherein X is a halogen atom and Rxe2x80x2 is a protective group for a hydroxyl group, with a base in the presence of a palladium catalyst, a phosphine ligand and a phase transfer catalyst(hereinafter referred to as xe2x80x9cProcess Fxe2x80x9d).
First a description will be made to the compound of the formula I.
The compound of the formula I above includes:
Compound [V]: 
Compound [VII]: 
Compound [VIIxe2x80x2a]: 
Compound [VIII]: 
wherein Rxe2x80x2, R10, R11, X and Ar are the same as defined above.
In the present specification, a chemical bond indicated by  means that the compound having the bond includes E isomer or Z isomer or both isomers with respect to a double bond connected to the said bond, and Compound [I] above has an optically active isomer and racemate thereof resulting from an asymmetric carbon atom present in the compound, which can be used in the following processes.
Examples of Ar group which may be substituted in the above formulas include a phenyl and naphthyl group which may be substituted.
Examples of the substituent include at least one substituent selected from a (C1-C5)alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, s-butyl, n-pentyl), a (C1-C5)alkoxy group (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, s-butoxy, n-pentoxy), a halogen atom(e.g., a fluorine, chlorine, bromine, or iodine atom), and a nitro group and the like.
Specific examples of Ar group which may be substituted include phenyl, naphthyl, o-tolyl, m-tolyl, p-tolyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-iodophenyl, m-iodophenyl, p-iodophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl and the like.
Examples of the protective group for a hydroxyl group for R, Rxe2x80x2, R1, R2 and R10 include:
an acyl group (an aliphatic or aromatic acyl group which may be substituted) such as acetyl, pivaloyl, benzoyl and p-nitrobenzoyl;
a silyl group such as trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl;
an alkoxymethyl group such as tetrahydrofuranyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl and 1-ethoxyethyl;
a benzyl group which may be substituted such as a benzyl group, a p-methoxybenzyl group and a trityl group;
a (C1-C6)lower alkyl group such as a t-butyl group, a methyl group;
a 2,2,2-trichloroethoxycarbonyl group;
an allyloxycarbonyl group and the like.
The acyl group described above may also includes those groups as defined for R11 and R12 below. The silyl group, alkoxymethyl group and a benzyl group described above may also include those defined for R12 below.
Next description will be made to each Process A to F for producing Compound [I] and Vitamin A.
Process A
Retinol of the formula [X] can be industrially advantageously produced by a process which comprises the steps of:
(a) reacting a compound of the formula [III] as defined above to a reaction in the presence of titanium tetrachloride, and
(b) reacting the resulting compound in step (a) with abase.
In step (a) an amount of titanium tetrachloride to be used is preferably 0.3-1.5 mol per mol of Compound [III].
In the above reaction, an organic solvent is usually used. Examples of the solvent include an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane and anisole; a hydrocarbon solvent such as n-hexane, cyclohexane, n-pentane, toluene and xylene;
a halogenated solvent such as chloroform, dichloromethane, 1,2-dichloroethane, monochlorobenzene and o-dichlorobenzene; and an aprotic polar solvent such as N,N-dimethyl formamide, dimethyl sulfoxide, N,N-dimethyl acetamide, hexamethylphosphoric triamide.
A reaction temperature usually ranges from xe2x88x9278xc2x0 C. to a boiling point of the solvent used, and preferably ranges from xe2x88x9210xc2x0 C. to 50xc2x0 C.
Next a description will be made to step (b).
Examples of the base used in this step include alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal hydride, alkaline earth metal hydride, alkali metal alkoxide and alkaline earth metal alkoxide, and specific examples thereof include sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, potassium t-butoxide, sodium t-butoxide and the like.
An amount of the base is usually about 2-20 mol per mol of the resulting compound in step (a).
In the above reaction, an organic solvent is usually used.
Examples of the solvent include a hydrocarbon solvent such as n-hexane, cyclohexane, n-pentane, toluene and xylene; an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane and anisole; and an aprotic polar solvent such as N,N-dimethyl formamide, dimethyl sulfoxide, N,N-dimethyl acetamide or hexamethylphosphoric triamide.
A reaction temperature is usually in the range from 0xc2x0 C. to a boiling point of the solvent used, preferably in the range from about xe2x88x9210xc2x0 C. to 50xc2x0 C. After the reaction, Compound of the formula [X] can be obtained by conducting a conventional post-treatment, and may be purified by silica gel chromatography or the like, if necessary.
After completion of the reaction, protective groups of the compound obtained by the aforementioned reaction may be removed, if necessary, to give an alcohol compound by a conventional deprotection reaction as described in Protective Groups in Organic Synthesis, Greene and Wuts, 2nd Edition, (1992), John Wiley and Sons, Inc., the complete disclosure of which is incorporated hereinafter by reference.
For example, when the protective group is an acyl group, the deprotection can be usually conducted by reacting the compound with a base.
Alkoxide of alkali metal or alkaline earth metal or the like can be used as abase. An amount of the base used is usually 1 equivalent or more to Compound of the formula [III].
N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, tetrahydrofuran, alcohol, a mixed solvent of alcohol and water, a mixed solvent of tetrahydrofuran, water and the like can be used as a reaction solvent.
The reaction is usually carried out at from 0xc2x0 C. to a boiling point of the reaction solvent used.
When the protective group is a silyl group or the like, the deprotection can be conducted by reacting the compound with tetra-n-butylammonium fluoride.
When the protective group is 2,2,2-trichloroethoxycarbonyl, a reductive deprotection can be performed using zinc dust and acetic acid.
Process B
Compound of the formula [III] can be produced by protecting a primary alcohol of Compound [IV].
The introduction of the protective group to the primary alcohol group of Compound of the formula [IV] is usually conducted by allowing Compound of the formula [IV] to react with a protective agent in the presence of a base and a phase-transfer catalyst.
The protective agent means a group consisting of a protective group and a leaving group (e.g., an active halogen atom or an acyloxy group) and includes an acyl halide, a benzyl halide which may be substituted, an alkoxymethyl halide, a silyl halide and an acid anhydride.
For example, the protective agent includes a compound of a formula: Rxe2x80x2Y, wherein Rxe2x80x2 is an acyl group, an alkoxymethyl group, a benzyl group which may be substituted or a silyl group which may be substituted with three groups selected from a phenyl and a (C1-C6)lower alkyl group, and Y is a halogen atom such as chlorine, bromine and iodine and when Rxe2x80x2 is an acyl group, Y may be an acyloxy group corresponding to the acyl group as defined for Rxe2x80x2 above.
The acyl group may be an aliphatic or aromatic acyl group which may be substituted, and may also include those groups as defined for R12 below. Specific examples thereof include acetyl, pivaloyl, benzoyl, p-nitrobenzoyl, 2,2,2-trichloroethoxycarbonyl and allyloxycarbonyl.
Examples of the alkoxymethyl group include methoxymethyl and methoxyethoxymethyl.
Examples of the benzyl group which may be substituted include a benzyl group, p-methoxybenzyl group and a trityl group.
Examples of the silyl group include trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and the like.
Among these, an acyl halide is preferably used. Acetyl chloride is particularly preferably employed.
Examples of the acid anhydride include acetic anhydride, propionic anhydride, butyric anhydride and the like, and acetic anhydride is preferably used.
The protective agent is usually used in an amount of about 0.1 to 1.1 mol, per mol of Compound of the formula [IV].
In this reaction, an organic base or an inorganic base is used as the base, and the inorganic base is preferably used.
Examples of the organic base include pyridine, 4-dimethylaminopyridine, 3-ethyl-4-methylpyridine, 5-ethyl-2-methylpyridine, imidazole, 2-methylimidazole, 3-methylimidazole, 2-ethyl-4-methylimidazole, DBU, trimethylamine, triethylamine, dimethylethylamine, methyldiethylamine, diisopropylethylamine, t-butyldimethylamine and the like.
Examples of the inorganic base include hydroxide of an alkali metal or an alkaline earth metal, a carbonate of an alkali metal or an alkaline earth metal, a hydrogencarbonate of an alkali metal or an alkaline earth metal and the like.
Specific examples of the inorganic base includes, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, calcium carbonate, calcium hydroxide and the like.
A solid inorganic base is preferably used in a fine powder form.
An amount of the base used usually ranges about 1-5 moles per mol of Compound of the formula [IV].
A phase-transfer catalyst is also usually employed.
Examples of the phase-transfer catalyst used in the reaction include a quaternary ammonium salt, a quaternary phosphonium salt, a sulfonium salt and the like, and the quaternary ammonium salt is preferably used.
As the quaternary ammonium salt, one comprising groups optionaly selected from alkyl and aryl having 1-24 carbon atoms is used.
Examples of the quaternary ammonium salt include, for example, tetramethylammonium chloride, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium chloride, tetrapentylammonium chloride, tetrahexylammonium chloride, tetraheptylammonium chloride, tetraoctylammonium chloride, tetrahexadecylammonium chloride, tetraoctadecylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, 1-methylpyridinium chloride, 1-hexadecylpyridinium chloride, 1,4-dimethylpyridinium chloride, tetramethyl-2-butylammonium chloride, trimethylcyclopropylammonium chloride, tetramethylammonium bromide, tetraethylammonium bromide, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrapentylammonium bromide, tetrahexylammonium bromide, tetraheptylammonium bromide, tetraoctylammonium bromide, tetrahexadecylammonium bromide, tetraoctadecylammonium bromide, benzyltrimethylammonium bromide, benzyltributylammonium bromide, 1-methylpyridinium bromide, 1-hexadecylpyridinium bromide, 1, 4-dimethylpyridinium bromide, trimethyl-2-butylammonium bromide, trimethylcyclopropylammonium bromide, benzyltriethylammonium bromide, tetramethylammonium iodide, tetrabutylammonium iodide, tetraoctylammonium iodide, t-butylethyldimethylammonium iodide, tetradecyltrimethylammonium iodide, hexadecyltrimethylammonium iodide, octadecyltrimethylammonium iodide, benzyltrimethylammonium iodide, benzyltriethylammonium iodide, benzyltributylammonium iodide and the like.
Examples of the quaternary phosphonium salt include tributylmethylphosphonium chloride, triethylmethylphosphonium chloride, methyltriphenoxyphosphonium chloride, butyltriphenylphosphonium chloride, tetrabutylphosphonium chloride, benzyltriphenylphosphonium chloride, hexadecyltrimethylphosphonium chloride, hexadecyltributylphosphonium chloride, hexadecyldimethylethylphosphonium chloride, tetraphenylphosphonium chloride, tributylmethylphosphonium bromide, triethylmethylphosphonium bromide, methyltriphenoxyphosphonium bromide, butyltriphenylphosphonium bromide, tetrabutylphosphonium bromide, benzyltriphenylphosphonium bromide, hexadecyltrimethylphosphonium bromide, hexadecyltributylphosphonium bromide, hexadecyldimethylethylphosphonium bromide, tetraphenylphosphonium bromide, tributylmethylphosphonium iodide, triethylmethylphosphonium iodide, methyltriphenoxyphosphonium iodide, butyltriphenylphosphonium iodide, tetrabutylphosphonium iodide, benzyltriphenylphosphonium iodide, hexadecyltrimethylphosphonium iodide.
Examples of the sulfonium salt include: dibutylmethylsulfonium chloride, trimethylsulfonium chloride, triethylsulfonium chloride, dibutylmethylsulfonium bromide, trimethylsulfonium bromide, triethylsulfonium bromide, dibutylmethylsulfonium iodide, trimethylsulfonium iodide, and triethylsulfonium iodide.
An amount of the phase-transfer catalyst used is usually within the range of about 0.01-0.2 mol, preferably about 0.02-0.1 mol per mol of Compound of the formula [IV].
In this reaction, an organic solvent is usually used. Examples of the solvent include:
a hydrocarbon solvent such as n-n-hexane, cyclon-hexane, n-pentane, toluene and xylene;
an ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane and anisole;
a halogenated solvent such as chloroform, dichloromethane, 1,2-dichloroethane, monochlorobenzene and o-dichlorobenzene; and
an aprotic polar solvent such as N,N-dimethyl formamide, dimethyl sulfoxide, N,N-dimethyl acetamide, hexamethylphosphoric triamide.
The reaction is usually carried out at temperature of from xe2x88x9278xc2x0 C. to aboiling point of the solvent used, and preferably ranges from 0xc2x0 C. to 30xc2x0 C.
The compound of the formula [IV] used above can be produced, for example, by deprotection according to a conventional method as described above in a procedure following step (b) of the compound of the formula [V] having two protected hydroxyl groups.
Process C
The compound of formula [V] can be obtained by a process which comprises reacting a sulfone compound of the formula [VI] with a halohydrin compound of the formula [VII] in the presence of a base.
In the halohydrin compound [VII], X indicates a halogen atom such as a chlorine atom, a bromine atom, an iodine atom or the like.
R10 indicates the same protective group as defined for Rxe2x80x2 above.
The compound of formula [VI] can be produced by a process as disclosed in Chemistry Letters, 1985, 479.
Examples of the base include alkyl lithium, a Grignard reagent, alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal hydride, alkaline earth metal hydride, alkali metal alkoxide and alkaline earth metal alkoxide.
Specific examples thereof include, n-butyllithium, s-butyllithium, t-butyllithium, ethylmagnesium bromide, ethylmagnisium chloride, sodium hydroxide, potassium hydroxide, sodiumhydride, potassium hydride, sodiummethoxide, potassium methoxide, potassium t-butoxide, sodium t-butoxide and the like.
An amount of the base is usually within the range of about 0.1-2 moles per mol of the sulfone compound of the formula [VI].
The phase-transfer catalyst as described above can be used in this reaction. An amount of the phase-transfer catalyst is usually within the range of about 0.01-0.2 mol, preferably about 0.02-0.1 mol per mol of the sulfone compound of the formula [VI].
In this reaction, an organic solvent is usually used. Examples of the solvent include an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane and anisole; a hydrocarbon solvent such as n-hexane, cyclohexane, n-pentane, toluene and xylene; and an aprotic polar solvent such as N,N-dimethyl formamide, dimethyl sulfoxide, N,N-dimethyl acetamide, hexamethylphosphoric triamide.
The reaction is usually carried out at temperature of from xe2x88x9278xc2x0 C. to a boiling point of the solvent used.
After completion of the reaction, the sulfone compound [V] can be obtained by a usual post-treatment and may be further purified by silica gel chromatography or the like, if necessary.
Process D
The halohydrin compound of the formula [VIIxe2x80x2] used above can be produced by a process which comprises reacting a compound of the formula: R12OH wherein R12 is an acyl group, with at least one compound selected from halohydrin compounds of the formulae of [VIIxe2x80x2a] and [VIIxe2x80x2b] in the presence of a strong acid catalyst.
In the halohydrin of the formula of [VIIxe2x80x2a] or [VIIxe2x80x2b] used in the this process, examples of the acyl group for R11 include formyl, acetyl, ethoxyacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, dibromoacetyl, tribromoacetyl, cyanoacetyl, propionyl, 2-chloropropionyl, 3-chloropropionyl, butyryl, 2-chlorobutyryl, 3-chlorobutyryl, 4-chlorobutyryl, 2-methylbutyryl, 2-ethylbutyryl, valeryl, 2-methylvaleryl, 4-methylvaleryl, hexanoyl, isobutyryl, isovaleryl, pivaloyl, benzoyl, o-chlorobenzoyl, m-chlorobenzoyl, p-chlorobenzoyl, o-acetoxybenzoyl, o-methoxybenzoyl, m-methoxybenzoyl and p-methoxybenzoyl. The acyl group for R11 may also include those listed for R12 below.
In the halohydrin compound of the formula of [VIIxe2x80x2a] or [VIIxe2x80x2b], Rxe2x80x2 indicates a protective group for a hydroxyl group.
Examples of the halogen atom for X include a chlorine atom, a bromine atom and an iodine atom.
Examples of the carboxylic acid of the formula R12OH include an aliphatic carboxylic acid having 1-6 carbon atoms and an aromatic carboxylic acid both of which may be substituted with a halogen atom(s), a (C1-C3)alkoxy group(s), a cyano group(s) or a (C1-C3)acyloxy group.
Specific examples of the aliphatic carboxylic acid include: formic acid, acetic acid, ethoxyacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, bromoacetic acid, dibromoacetic acid, tribromoacetic acid, cyanoacetic acid, propionic acid, 2-chloropropionic acid, 3-chloropropionic acid, n-butyric acid, 2-chloro-n-butyric acid, 3-chloro-n-butyric acid, 4-chloro-n-butyric acid, 2-methyl-n-butyric acid, 2-ethyl-n-butyric acid, n-valeric acid, 2-methyl-n-valeric acid, 4-methyl-n-valeric acid, hexanoic acid, isobutyric acid, isovaleric acid, pivalic acid.
Examples of the aromatic carboxylic acid include: benzoic acid, o-chlorobenzoic acid, m-chlorobenzoic acid, p-chlorobenzoic acid, acetylsalicylic acid, o-anisic acid, m-anisic acid and p-anisic acid. An amount thereof is not particularly limited.
As the strong acid catalyst, an organic acid such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid and trifluoroacetic acid; strong acid cation-exchange resins such as Nafion (trade mark), Amberlyst (trade mark) and Duolite (trade mark); inorganic acids such as sulfuric acid, hydrochloric acid and perchloric acid are used.
An amount of the strong acid catalyst is usually within the range of about 0.01-0.5 mol, preferably about 0.05-0.3 mol per mol of the halohydrin compound of the formula [VIIxe2x80x2a] or [VIIxe2x80x2b].
The reaction is usually carried out at temperature of from xe2x88x9278xc2x0 C. to a boiling point of the solvent used, preferably about 10-30xc2x0 C.
After completion of the reaction, for example, water is added to the reaction mixture and the mixture is subjected to extraction, phase separation, and concentration of the organic layer to obtain the halohydrin compound of the formula [VIIxe2x80x2], which may be further purified by silica gel chromatography, if necessary.
Process E
At least one compound selected from the halohydrin compound of the formula of [VIIxe2x80x2a] and [VIIxe2x80x2b] can be produced by allowing a triene compound of the formula [VIII] to react with a compound of R11OH wherein R11 is a hydrogen atom or an acyl group, and a halogenating agent.
Examples of the halogenating agent include a chlorinating agent such as chlorine, hypochlorous acid, t-butyl hypochlorite, ethyl hypochlorite, sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, N-chlorourea, N-chlorosuccinimide, chloramine-T and chloramine-B; brominating agents such as a bromine, hypobromous acid, calcium hypobromite, N-bromoacetamide and N-bromosuccinimide; and iodinating agents such as an iodine and N-iodosuccinimide.
An amount of the halogenating agent is not particularly restricted, but about one mol of halogenating agent per mol of the triene compound of the formula [VII] is usually used.
As a reaction solvent, an ether such as tetrahydrofuran, dioxane, dimethoxyethane and diethyl ether; an alcohol such as t-butyl alcohol, t-amyl alcohol and 2-propanol; a halogenated hydrocarbon such as dichloromethane, chloroform and carbon tetrachloride; a ketone such as acetone, methyl isopropyl ketone and methyl isobutyl ketone, an aprotic polar solvent such as dimethyl sulfoxide, acetonitrile, N,N-dimethyl formamide and N,N-dimethyl acetamide. An amount of the solvent is not particularly limited.
When R11 indicates an acyl group, the acyl group include those described for R12 above.
An amount of the carboxylic acid is not particularly limited, but it is usually within the range from about 1 mol to about 10 moles per mol of the triene compound [VIII].
The reaction is usually carried out within a temperature range from about 15 to 120xc2x0 C.
In this process water can be used in place of the carboxylic acid, R11 indicating a hydrogen atom. An amount of water is usually in the range of about 1-100 moles, preferably in the range of about 1-10 moles per mol of the triene compound of the formula [VII]. The reaction is usually carried out at temperature of from xe2x88x9278xc2x0 C. to a boiling point of the solvent used, preferably 0-30xc2x0 C.
After completion of the reaction, the halohydrin compounds [VII xe2x80x2a] and [VIIxe2x80x2b] can be obtained by a conventional post-treatment. These regio isomers can be separated and purified by silica gel chromatography.
When the halohydrin compound [VII] has a protective group other than an acyl group for R10, such a halohydrin compound can be obtained by protecting either a hydroxyl group of the halohydrin compounds [VIIxe2x80x2b] wherein R11 is a hydrogen atom, or that obtained by deprotecting the acyl group R12 of the halohydrin compound [VIIxe2x80x2].
The deprotection is usually conducted according to a deprotecting process as described above following Process A.
Process F
The triene compound of the formula [VIII] can be produced by a process which comprises reacting a compound of the formula [IX] with a base in the presence of a palladium catalyst.
An alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in a form of fine powder is usually used in this reaction. An amount of the base used is usually about 1-5 moles per mol of the compound of the formula [IX].
Examples of the palladium catalyst include allylpalladium chloride dimer, palladium acetate, palladium oxide, palladium propionate, dichlorobis(triphenylphosphine)palladium, palladium di-xcexc-chlorobis (xcex7-allyl), palladium dichloro (xcex7-1, 5-cyclooctadiene), palladium dichloro (xcex7-2, 5-norbornadiene), palladium dichlorobis(acetonitrile), palladium dichlorobis(benzonitrile), palladium dichlorobis(N,N-dimethyl formamide), palladium bis(acetylacetonato) and the like. Allylpalladium chloride dimer is particularly preferably used.
An amount of the palladium catalyst is usually 0.05% by weight or more, preferably 1% by weight or more per mol of the compound [IX]. Although the upper limit is not restricted, it is preferably 5% by weight of less for economic reasons.
The reaction is usually carried out in the co-presence of a phase-transfer catalyst in order to accelerate the reaction.
Examples of the phase-transfer catalyst include a quaternary ammonium salt, a quaternary phosphonium salt and a sulfonium salt as described above.
An amount of the phase-transfer catalyst is usually 0.01-0.1 part by weight, preferably 0.02-0.1 part by weight of Compound [IX].
An anhydrous solvent is usually used in this reaction, and examples thereof include an aprotic polar solvent such as N,N-dimethyl formamide, dimethyl sulfoxide and N,N-dimethyl acetamide; an ether such as diethyl ether and tetrahydrofuran; an aromatic hydrocarbon such as toluene and xylene; an ester such as ethyl acetate or methyl formate; a ketone such as acetone; and an alcohol such as methanol, ethanol, i-propyl alcohol or t-butyl alcohol. The reaction is usually carried out at temperature from about 10xc2x0 C. to a boiling temperature of the solvent used.
After completion of the reaction, the triene compound [VIII] can be obtained by a conventional post-treatment, and may be further purified by silica gel chromatography, if necessary.
A compound of the formula [IX] can by easily synthesized by a known method.